Comment on Moriconi et al. Very-Low-Calorie Ketogenic Diet as a Safe and Valuable Tool for Long-Term Glycemic Management in Patients with Obesity and Type 2 Diabetes. Nutrients 2021, 13, 758.

With interest, we have read the article of Moriconi et al. [...].

Ketogenic diet treatment as adjuvant to standard treatment of glioblastoma multiforme: a feasibility and safety study.

BACKGROUND: High-grade glioma cells consume mainly glucose and cannot compensate for glucose restriction. Apoptosis may potentially occur under carbohydrate restriction by a ketogenic diet (KD). We explored the feasibility and safety of KD during standard treatment of chemoradiation in patients with glioblastoma multiforme. METHODS: A full liquid KD induced ketosis within 2 weeks before start of chemoradiation. After 6 weeks, the KD was modified with solid foods and medium-chain-triglyceride emulsions and used for an additional 6 weeks while maintaining ketosis. During the total study period (14 weeks), feasibility, safety, coping (both patient and partner), quality of life (QoL), neurological functioning and impairment were measured. Overall survival was analyzed with actuarial estimates. RESULTS: Eleven patients started the study protocol, nine reached ketosis and six (67%) completed the study. Severe adverse effects did not occur. The majority of coping scores ranged from 3 to 6 on a 10-point scale at all timepoints; QoL, neurological functioning, and impairment did not essentially change over time; overall survival ranged between 9.8 and 19.0 months. CONCLUSION: KD was feasible and safe as an adjuvant to standard chemoradiation treatment of glioblastoma multiforme. A supportive partner and intensive counseling were essential for coping. Future research should identify possible beneficial effects on overall survival. CLINICAL TRIAL REGISTRATION: Netherlands Trial Registry: NTR5167 (registration date 29-01-2015), http://www.trialregister.nl/trialreg/index.asp.

Ketogenic diet treatment in recurrent diffuse intrinsic pontine glioma in children: A safety and feasibility study.

BACKGROUND: The mean overall survival rate of children with diffuse intrinsic pontine glioma (DIPG) is 9-11 months, with current standard treatment with fractionated radiotherapy and adjuvant chemotherapy. So far, novel therapeutic strategies have not yet resulted in significantly better survival. The main source of energy for glioblastoma cells is glucose. Therefore, metabolic alterations induced by the use of the extremely carbohydrate-restricted ketogenic diet (KD) as adjuvant therapy are subject of interest in cancer research. PROCEDURE: This study explores the safety and feasibility of the KD in children with recurrent DIPG and no remaining treatment options. Safety was defined as the number of adverse effects. Feasibility was defined as the number of patients who were able to use the KD for three months. Coping of patients and parents was measured with questionnaires. RESULTS: Three of 14 children referred to our hospital between 2010 and 2015 were included. Two patients completed the study, and one died before the end of the study. Hospitalizations were needed for placing a nasogastric tube (n = 1) and epileptic seizures (n = 1). Adverse effects related to the diet were mild and transient. Parents were highly motivated during the study. CONCLUSION: Use of KD is safe and feasible, but the effect on survival has to be proven in a larger cohort of children who start the KD earlier after diagnosis, preferably as adjuvant therapy to fractionated radiotherapy.

Optimal clinical management of children receiving dietary therapies for epilepsy: Updated recommendations of the International Ketogenic Diet Study Group.

Ketogenic dietary therapies (KDTs) are established, effective nonpharmacologic treatments for intractable childhood epilepsy. For many years KDTs were implemented differently throughout the world due to lack of consistent protocols. In 2009, an expert consensus guideline for the management of children on KDT was published, focusing on topics of patient selection, pre-KDT counseling and evaluation, diet choice and attributes, implementation, supplementation, follow-up, side events, and KDT discontinuation. It has been helpful in outlining a state-of-the-art protocol, standardizing KDT for multicenter clinical trials, and identifying areas of controversy and uncertainty for future research. Now one decade later, the organizers and authors of this guideline present a revised version with additional authors, in order to include recent research, especially regarding other dietary treatments, clarifying indications for use, side effects during initiation and ongoing use, value of supplements, and methods of KDT discontinuation. In addition, authors completed a survey of their institution's practices, which was compared to responses from the original consensus survey, to show trends in management over the last 10 years.

Ketogenic diet therapy for epilepsy during pregnancy: A case series.

PURPOSE: Evaluation of ketogenic diet (KD) therapies for seizure control during pregnancy when safety and appropriate management become considerations. Until now, no information has been available on seizure reduction and human pregnancy related outcomes in women treated with KD therapies. METHOD: We describe two cases of pregnant women with epilepsy treated with KD therapy either as monotherapy (Case 1) or as adjunctive therapy (Case 2). RESULTS: Case 1: A 27 year old woman, gravida1, started the classic KD with medium chain triglyceride (MCT) emulsion and 75g carbohydrate-restriction, later reduced to 47g. Glucose levels were 4-6mmol/L and blood ketone levels ranged from 0.2 to 1.4mmol/L. Seizure frequency decreased and seizure-free days increased. Mild side effects included intolerance to MCT, reduced serum carnitine and vitamin levels, and mild hyperlipidemia. Fetal and neonatal growth was normal as was growth and development at 12 months. Case 2: A 36 year-old nulliparous woman was treated with a 20 gram carbohydrate-restricted Modified Atkins Diet (MAD) and lamotrigine, resulting in reduction of seizure frequency to once per month prior to pregnancy. Once pregnant, carbohydrates were increased to 30g. When seizures increased, lamotrigine dose was doubled. Urine ketones trended down during second trimester. A male was born with bilateral ear deformities of unknown significance. The child had a normal neurodevelopment at eight months. CONCLUSION: Non-pharmacological epilepsy therapies like KD and MAD may be effective during human pregnancy. However, safety still has to be established. Further monitoring to identify potential long term side effects is warranted.

Concomitant lamotrigine use is associated with decreased efficacy of the ketogenic diet in childhood refractory epilepsy.

PURPOSE: Anti-epileptic drugs (AEDs) and the ketogenic diet (KD) are often used concomitantly in children with refractory epilepsy. It has been hypothesised that certain AEDs may interfere with KD. The purpose of this study was to elucidate relationships between efficacy of KD and use of specific AEDs. METHODS: A retrospective study was performed in 71 children with refractory epilepsy starting the KD between 2008 and 2014 in Erasmus University Hospital Sophia Children's Hospital. Efficacy of the KD (defined as 50% seizure reduction) was evaluated after three months of treatment and related to the AEDs used. RESULTS: The KD was successful after three months in 61% of the children (N=71). Efficacy was significantly reduced if children (n=16) used lamotrigine (31%) at diet initiation or in the course of the diet, compared to other antiepileptic drugs (69%) (p=0.006). In comparison to children using other antiepileptic drugs, the percentage of children that had adequate ketosis was significantly reduced in case of lamotrigine use (p=0.049). CONCLUSION: Lamotrigine treatment during KD is associated with a decreased efficacy of the KD.

Can we predict efficacy of the ketogenic diet in children with refractory epilepsy?

BACKGROUND: The ketogenic diet (KD) can be effective in reducing seizures in children. Predictors of success have not been identified yet. AIMS: To evaluate efficacy of KD treatment and to search for child- or diet-related factors that can predict its efficacy at 12 months follow-up. In addition we wish to determine the usefulness of a 3-month KD trial period. METHODS: Single center retrospective study in a university paediatric hospital of children with refractory epilepsy in which the KD had been initiated. Patient and diet characteristics as well as seizure reduction data were obtained from medical records and parental review. Efficacy of the KD was defined as ≥ 50% seizure reduction. Variables were evaluated in their relation to a successful treatment at three and 12 months after diet initiation. RESULTS: During a 9.5-year period, the KD was initiated in 59 children with refractory epilepsy. Twenty-four children were still on the KD after 12 months, and 21 experienced ≥50% seizure reduction. Success of the KD at three months was significantly related to a successful response to KD treatment at 12 months (p < 0.001). CONCLUSIONS: The KD can be an effective treatment in reducing seizures in children with refractory epilepsy. No significant relationships between variables and efficacy at 12 months were revealed. Children with a successful response at 3 months were significantly more likely to achieve success at 12 months of KD treatment.

Germline activating AKT3 mutation associated with megalencephaly, polymicrogyria, epilepsy and hypoglycemia.

Activating germ-line and somatic mutations in AKT3 (OMIM 611223) are associated with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH; OMIM # 615937) and megalencephaly-capillary malformation (MCAP; OMIM # 602501). Here we report an individual with megalencephaly, polymicrogyria, refractory epilepsy, hypoglycemia and a germline AKT3 mutation. At birth, head circumference was 43 cm (5 standard deviations above the mean). No organomegaly was present, but there was generalized hypotonia, joint and skin laxity, developmental delay and failure to thrive. At 6 months of age the patient developed infantile spasms that were resistant to antiepileptic polytherapy. Recurrent hypoglycemia was noted during treatment with adrenocorticotropic hormone but stabilized upon introduction of continuous, enriched feeding. The infantile spasms responded to the introduction of a ketogenic diet, but the hypoglycemia recurred until the diet was adjusted for increased resting energy expenditure. A novel, de novo AKT3 missense variant (exon 5; c.548T>A, p.(V183D)) was identified and shown to activate AKT3 by in vitro functional testing. We hypothesize that the sustained hypoglycemia in this patient is caused by increased glucose utilization due to activation of AKT3 signaling. This might explain the efficacy of the ketogenic diet in this individual.